Numerous metabolic bone disorders are known which are characterized by loss of bone mass or bone mineral. These disorders include postmenopausal osteoporosis, senile osteoporosis, corticosteroid-induced osteopenia, anticonvulsant osteomalacia and renal osteodystrophy. Of these disorders, renal osteodystrophy is encountered in end-stage renal disease patients undergoing chronic dialysis.
As a group, these bone depletive disorders are a major and growing public health problem in the United States. Together, they cause more than 1 million bone fractures per year, primarily of the spine, hip, and distal forearm, and result in an annual cost above $10 billion to the American society. Unfortunately, the incidence of these bone disorders will rise significantly as the mean age of the U.S. population continues to increase.
Despite differing etiologies, the aforementioned metabolic bone disorders develop during an extended period of negative calcium balance. This commonality of the disorders suggests that agents which stimulate intestinal calcium absorption and otherwise regulate calcium homeostasis may be effective in restoring calcium balance, thereby treating or preventing the development of such bone disorders.
It has long been known that vitamin D plays a critical role in stimulating calcium absorption and regulating calcium metabolism. The discovery of the active forms of vitamin D in the 1970's [M. F. Holick et al., Proc. Natl. Acad. Sci. USA 68, 803-804 (1971); G. Jones et al., Biochemistry 14, 1250-1256 (1975)] and active vitamin D analogues [M. F. Holick et al., Science 180, 190, 191 (1973); H. Y. Lam et al., Science 186, 1038-1040 (1974)], caused much excitement and speculation about the usefulness of these compounds in the treatment of bone depletive disorders.
Animal and early clinical studies examining the effects of these active vitamin D compounds suggested that such agents would be useful in restoring calcium balance. However, the best indicator of the efficacy of vitamin D compounds to prevent or treat depletive bone disorders is bone itself (or, in the case of renal osteodystrophy, serum levels of parathyroid hormone (PTH)) rather than calcium absorption or calcium balance. Certain clinical studies with 1.alpha.,25-(OH).sub.2 vitamin D.sub.3, and 1.alpha.-OH vitamin D.sub.3 indicate that the ability of these agents to restore lost bone mass or bone mineral content is dose related. [See, S. M. Ott, C. H. Chesnut, Annals of Int. Med. 1989; 110:267-274; J. C. Gallagher et al., Annals of Int. Med. 1990; 113:649-655; J. Aloia et al., Amer. J. Med. 84:401-08 (1988)] M. Shiraki et al., Endocrinol. Japan 32, 305-315 (1985)].
These studies also indicate that at the dosage ranges required for these agents to be truly effective, toxicity in the form of hypercalcemia and hypercalciuria becomes a major problem. Attempts to increase the amount of 1.alpha.,25-(OH).sub.2 vitamin D.sub.3 above 0.5 .mu.g/day have frequently resulted in toxicity. At dosage levels below 0.5 .mu.g/day, clinically significant effects are rarely observed on bone. [See G. F. Jensen et al., Clin. Endocrinol. 16, 515-524 (1982); C. Christiansen et al., Eur. J. Clin. Invest. 11, 305-309 (1981)]. Doses of 2 .mu.g/day of 1.alpha.-OH vitamin D.sub.3 were found to have efficacy in increasing bone mass in patients exhibiting senile osteoporosis [O. H. Sorensen et al., Clin. Endocrinol. 7, 169S-175S (1977)]. Data from clinical studies in Japan, a population that has low calcium intake, indicate that efficacy is found with 1.alpha.-OH vitamin D.sub.3 when administered at 1 .mu.g/day [M. Shiraki et al., Endocrinol. Japan. 32:305-315 (1985); H. Orimo et al., Bone and Mineral 3, 47-52 (1987)]. However, at 2 .mu.g/day, toxicity with 1.alpha.-OH vitamin D.sub.3 occurs in approximately 67 percent of the patients, and at 1 .mu.g/day this percentage is approximately 20 percent.
Thus, the prior art teaches that due to their toxicity, 1-hydroxylated vitamin D compounds can only be administered at dosages that are, at best, modestly beneficial in preventing or treating loss of bone or bone mineral content. Indeed, Aloia recommends that alternative routes of administration be sought which might avoid the toxicity problems and allow higher dosage levels to be achieved. [J. Aloia et al., Amer. J. Med. 84:401-408 (1988)].
Despite reported toxicities of 1.alpha.-OH vitamin D.sub.3 and 1.alpha.,25-(OH).sub.2 vitamin D.sub.3, these two compounds remain the drugs of choice for many bone depletive disease treatments. For example, in end stage renal disease, these two drugs remain the only approved forms of 1.alpha.-hydroxylated vitamin D for treating or preventing secondary hyperparathyroidism, although both drugs are not currently approved in all major pharmaceutical markets.
At present, in the United States, end stage renal disease afflicts approximately 200,000 individuals. In this disease, there is a progressive loss of cells of the proximal nephrons, the primary site for the synthesis of the vitamin D hormones (collectively "1.alpha.,25-(OH).sub.2 D") from 25-hydroxyvitamin D.sub.3 and 25-hydroxyvitamin D.sub.2. In addition, the loss of functioning nephrons leads to retention of excess phosphorus which reduces the activity of the renal 25-hydroxyvitamin D-1.alpha.-hydroxylase, the enzyme which catalyzes the reaction to produce the D hormones. These two events account for the low serum levels of 1.alpha.,25-(OH).sub.2 D commonly found in patients with mild to moderate end stage renal disease.
Reduced serum levels of 1.alpha.,25-(OH).sub.2 D cause increased, and ultimately excessive, secretion of PTH by direct and indirect mechanisms. The resulting hyperparathyroidism leads to markedly increased bone turnover and its sequela of renal osteodystrophy, which may include a variety of other diseases, such as, osteitis fibrosa cystica, osteomalacia, osteoporosis, extraskeletal calcification and related disorders, e.g., bone pain, periarticular inflammation and Mockerberg's sclerosis. Reduced serum levels of 1.alpha.,25-(OH).sub.2 D also can cause muscle weakness and growth retardation with skeletal deformities (most often seen in pediatric patients).
All previous clinical studies of hormonally active vitamin D drugs in end stage renal disease patients have focused exclusively on compounds derived from vitamin D.sub.3. Use of 1.alpha.,25-(OH).sub.2 D.sub.3 and 1.alpha.-OH-vitamin D.sub.3 as replacement therapy seeks to treat or prevent renal osteodystrophy by treating or preventing secondary hyperparathyroidism in end stage renal disease patients. As noted above, 1.alpha.,25-(OH).sub.2 D.sub.3 often causes toxic side effects (hypercalcemia and hyperphosphatemia) at dosages above 0.5 .mu.g, especially when concomitantly administered calcium phosphate binders are used to control serum phosphorus. The minimum effective dose for preventing secondary hyperparathyroidism is in the range of 0.25 to 0.50 .mu.g/day; most patients respond to oral treatment doses of 0.5 to 1.0 .mu.g/day or intravenous doses between 0.5 and 3.0 .mu.g three times per week. As described above, the other commonly used vitamin D drug is 1.alpha.-OH-D.sub.3 which often causes toxic effects at dosages over 1.0 .mu.g/day, especially when used with calcium phosphate binders. The minimum effective dosage for preventing secondary hyperparathyroidism is in the range of 0.25 to 1.0 .mu.g/day, and most patients require treatment dosages of 1.0 .mu.g/day or more. When either drug, 1.alpha.,25-(OH).sub.2 D.sub.3 or 1.alpha.-OH-D.sub.3, is administered in higher dosages, both efficacy and toxicity are found to increase. Thus, the hormonally active vitamin D.sub.3 compounds are limited in their therapeutic usefulness due to their inherent toxicities.
To reduce the incidence of toxic side effects with 1.alpha.,25-(OH).sub.2 D.sub.3 or 1.alpha.-OH-D.sub.3, a low calcium dialysate with an ionized calcium concentration of 1.25 mM has been developed. However, it has been found that use of the low calcium dialysate has lead to higher serum PTH and phosphorus levels in patients who do not receive increased doses of oral calcium supplements and phosphate binders. When the dosages of calcium supplements and phosphate binders are increased, serum levels of phosphorus become controlled, but the incidence of hypercalcemia rises markedly. Thus, there are many problems associated with the use of current vitamin D therapies for secondary hyperparathyroidism.
Notwithstanding these known problems with use of the hormonally active vitamin D.sub.3 for secondary hyperparathyroidism, the art has not adequately responded to date with the introduction of other vitamin compounds, derivatives or analogs that possess less inherent toxicity.